The Class I alcohol dehydrogenases (ADH) and the cytosolic and mitochondrial aldehyde dehydrogenases (ALDHl and ALDH2) play major roles in ethanol and acetaldehyde oxidation. The genetic variations of these enzymes would affect the clearance of the toxic chemicals and alcohol intoxication, and indirectly affect the development of alcohol-related diseases. The racial differences in the incidence of alcohol sensitivity and alcoholism may be, in Part, attributed to the genetic background. The overall objectives of the Project are: to elucidate the genomic structures and gene expressions of ADH and ALDH; to examine their genetic variations and identify their mutation sites, and to elucidate the correlations of these genetic variations to alcoholic-related problems. The following projects will be undertaken: 1) Determination of the genomic structure of ADH cluster locus, which includes three genes, i.e. ADH, (for alpha-subunit), ADH1 (for beta-subunit), and ADH1 (for gamma-subunit), their 3'- and 5'- regions, and possibly pseudogene(s); 2) Study of developmental regulation of expression of the cytosolic ALDH1 and the mitochondrial ALDH2 loci, by analyzing translation products and quantity and quality of primary transcripts and mRNAs in fetal and adult livers; 3) Determination of the genotypes of ADH2 and ALDH2 loci in subjects with alcoholic diseases and control subjects in Caucasians, Orientals (Japanese and Koreans) and American Indians, and examination of restriction fragment length polymorphism of the loci in these populations; and 4) Exploration and characterization of the cytosolic ALDHl variants related to alcohol sensitivity and other alcoholic problems.